Certain bis-(hydroxyalkyl)esters of 1,4-dihydro-2,6-diloweralkyl-4-(2-trifluoromethylphenyl)pyridine-3, 5 dicarboxylic acid and the N-methyl derivative thereof

ABSTRACT

The compounds are 1,4-dihydropyridines having anti-hypertensive activity. A particular compound of this invention is 1,4-dihydro2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylic acid bis-(2-hydroxyethyl)ester.

United States Patent [1 1 [111 3,910,937 Roe et al. Oct. 7, 1975 CERTAIN BIS-(HYDROXYALKYL)ESTERS [58] Field of Search 260/2955 R l,4-DIHYDRO-2,6-DILOWERALKYL-4-(2- [56] References Cited TRIFLUOROMETI-IYLPHENYL)PYRIDINE- 3, 5 DICARBOXYLIC ACID AND THE N-METIIYL DERIVATIVE THEREOF Inventors: Anthony Maitland Roe, Hatfield;

Robert Antony Slater, Letchworth, both of England; Bernard Loev, Broomall, Pa.

Assignee: Smith Kline & French Laboratories Limited, Welwyn Garden City, England Filed: June 5, 1974 Appl. No.: 476,346

Foreign Application Priority Data June l2, I973 United Kingdom 27793/73 US. Cl. 260/2955 R; 424/266 Int. Cl. C07D 211/90 OTHER PUBLICATIONS Loev et al., Chem. Abstracts, Vol. 78, (1973), 92394, Bossert et al., Chem. Abstracts, Vol. 70, (1969), 87580.

Bossert et al., Chem. Abstracts, Vol. 70, ([969), 96641.

Primary ExaminerI-Ienry R. Jiles Assistant ExaminerBernard I. Dentz Attorney, Agent, or FirmJ0an S. Keps; Richard D. Foggio; William H. Edgerton [57] ABSTRACT The compounds are l,4-dihydropyridines having anti' hypertensive activity. A particular compound of this invention is l,4-dihydro-2,6-dimethyl-4-( 2- trifluoromethylphenyl)pyridine-3,5-dicarboxylic acid bis-(2-hydroxyethyl)ester.

4 Claims, No Drawings CERTAIN BIS-( HYDROXYALKYL )ESTERS OF 1 .4-DIHYDRO-2,6-DILOWERALKYL-4-( 2- TRIFLUOROMETHYLPHENYL)PYRIDINE-l DICARBOXYLIC ACID AND THE N-METHYL DERIVATIVE THEREOF This invention relates to l,4-dihydropyridine compounds to methods for their preparation and to phar maceutical compositions comprising these compounds.

The 1.4-dihydropyridine compounds of the present invention are useful as water-soluble antihypertensive agents which act primarily as precapillary vasodilators.

Throughout the present specification, by the term lower alkyl we mean an alkyl group containing from l to 4 carbon atoms.

According to the present invention we provide compounds of the following general formula I:

3 HO-A-O-CO CO-O-A-OH a N R FORMULA I wherein R is lower alkyl, R is hydrogen or methyl, and A is a straight or branched alkylenc chain the backbone of which contains from 2 to 4 carbon atoms.

A particular useful compound is that wherein each R is methyl, R is hydrogen and A is LZ-ethylene.

The compounds of our invention may be produced by a process wherein Z-trifluoromethylbenzaldehyde is reacted with an acyl fatty acid ester of the Formula ll:

wherein R and A have the above significance and Q is hydrogen or at protecting group such as benzyl, in the presence of ammonia or a lower alkyl amine. This reaction may be carried out in a solvent such as ethanol under reflux conditions. The protecting group. if used, may then be removed by suitable means e.g., by hydrogenolysis in the ease of a benzyl protecting group. to give the required compound of Formula I.

In an alternative process the Z-trifluoromethylbenzaldehyde is reacted with a compound of the Formula lll:

FORMULA lll wherein R, R and A have the same significance as in Formula I and O has the same significance as in Formula ll. As in the first mentioned process, any protecting group will of course be removed to give the required compound. A solvent such as acetic acid or ethanol may also be used.

Compounds of Formula I wherein R is methyl may also be produced by treatment in the presence of a base 5 such as sodium hydride of a compound of Formula I wherein R is hydrogen with a methyl halide. This reaction may be carried out in a solvent such as dimethylformamide.

The pharmacological activity of our compounds may It) be demonstrated in conscious cannulated normotensive dogs wherein dose-dependent hypotension results from the oral administration of from 2.5 to mg/kg of our compounds, and in rats wherein an increased flow rate is observed in the hindquarters, perfused at 15 constant pressure, on the intravenous administration of 0.8 mg/kg of our compounds.

Our invention also provides pharmaceutical compositions comprising a compound of Formula I together with a pharmaceutically acceptable diluent or carrier. Advantageously the compositions will be made up in a dosage unit form appropriate to the desired mode of administration. The pharmaceutical carrier employed may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin. acacia, magnesium stearate and stearic acid. Exemplary of liquid carriers are syrup, peanut oil, olive oil and water, the latter being particularly preferred because of the water solubility of the compounds of Formula I and because of the great utility for injectible use of such aqueous solutions. Other pharmacologically active compounds may in certain cases be included in the pharmaceutical compositions.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a trochc or lozenge. The amount of solid carrier will vary widely but preferably will be from about mg to about 1 gm. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or a sterile injectible liquid, preferably water, which may be prepared in an ampoule.

The pharmaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. The active ingredients will be present in the composition in an effective amount to produce the required anti-hypertensive effect. The route of administering may 50 be orally or parenterally e.g., sub-cutaneously or intravenously.

Advantageously the composition will be made up in a dosage form appropriate to the desired mode of administration, for example, as a tablet, capsule or injectablc solution.

The invention is illustrated but in no way limited by the following examples:

EXAMPLE I Preparation of l,4-dihydro-2,6-dimethy|-4-( 2- trifluoromethylphenyl )pyridine-3,S-dicarboxylic acid bis (2-hydroxyethyl J-estcr.

i. A mixture of acetoacetic ester (l3.() g) and 2- benzyloxyethanol (22.0 g) was stirred under reflux for 30 minutes. Distillation under vacuum yielded the crude product (2 l .5 g) which on re-distillation gave, as

a colourless oil, acetoaeetic acid 2-benzyloxyethyl ester (l7.2 g), b.p. l24C/().l mm.

ii. A mixture of acetoacetic acid 2-benzyloxyethyl ester (30 g), o-trifluoromethyl benzaldehydc (11.2 g) and concentrated ammonia (8.0 ml of density 0.88) in ethanol 100 ml) was stirred under reflux for 24 hours and then poured into ice and water. The yellow oil which precipitated was separated, and solidified on addition of ethanol. Recrystallisation from ethanol gave l,4-dihydro-2,6-dimethyl-4- (Z-trifluoromethylphenyl )pyridine 3,5-dicarboxylic acid bis-(2-benzyloxyethyl)ester 10.4 g), as white crystals m.p. l4l142C.

iii. The bis-benzyl ether, produced in (ii) above, (8 g) was dissolved in ethanol and hydrogenated over palladium charcoal, Evaporation of dryness of the filtrate. produced on the removal of the catalyst, and recrystallisation of the residue, first from isopropyl acetate and then from ethanol gave l,4-dihydro-2,6-dimethyl-4-(2- trifluoromethylphenyl)pyridine-3,S-dicarboxylic acid bis-(2-hydroxyethyl)ester (4.6 g) m.p. l I27".

EXAMPLE 2 Preparation of l .4-dihydrol ,2,6-trimethyl-4-( ltrifluoromethylphenyl)pyridine-3,S-dicarboxylic acid bis (Z-hydroxyethyl )ester.

i. To a stirred solution of l,4-dihydro-2,6-dimethyl- 4-( Z-trifluoromethylphenyl )pyridine-3 ,S-dicarboxylic acid bis (2-benzyloxethyl)ester 18.2 g.) in dry dimethylformamide (100 ml) was added in portions sodium hydride (L38 g. of a 60 percent dispersion in oil). When the mixture had been stirred for a further 60 minutes at room temperature methyl iodide (30 ml) was added and stirring was continued for another hour. The reaction mixture was then treated with saturated ammonium chloride solution (150 ml) and the resulting solution extracted with ether. Evaporation of the dried extracts gave an oil which was purified by column chromatography to give as a pale yellow oil 1,4- dihydro-l ,2,6-trimethyl-4-( 2-trifluoromethylphenyl)- pyridine-3 .S-dicarboxylic acid bis( Z-benzyloxyethyl)ester (6.0 g).

ii. The bis-benzyl ether produced in (i) above (5.7 g) was hydrogenated over palladium-charcoal as de scribed in Example 1 to give. after purification by column chromatography and recrystallisation from aqueous ethanol, l,4-dihydro-l ,2,6-trimethyl-4- (2-trifluoromethylphenyl )pyridine-3.S-dicarboxylic acid bis (2-hydroxyethyl)ester (L! g) as colourless crystals m.p. I20 l22C.

EXAMPLE 3 Preparation of l,4-dihydro-2.6-dimethyl-4-( Z-trifiuoromethylphenyl pyridine-3.S-dicarboxylic acid bis( 3-hydroxy-2-propyl )ester i. A mixture of acetoacetic ester (l9.0 g) and 3- benzyloxy-Z-propanol (32.0 g) were stirred under reflux for 2 hours. Fractional distillation under vacuum gave. as a colourless oil, acetoacetic acid (S-benzyloxy- 2-propyl) ester l5.2 g), b.p. l3()- lC/().l mm.

ii. A mixture of acetoacetic acid (3-benzyloxy-2- propyl) ester (23.8 g), o-trifluoromethylbenzaldchyde (8.7 g.) and concentrated ammonia l0.() ml. of density 0.88) in ethanol (200 ml) was stirred under reflux EXAMPLE 4 Preparation of l .4-dihydro-2,6-dipropyl-4-( 2-trifluoroomethylphcnyl)-pyridine-3,5-dicarboxylie acid bis (Z-hydroxyethyl )ester Reaction of butyroacetic ester and 2- benzyloxyethanol by the procedure of Example l(i) gives butyroacetic acid Z-benzyloxyethyl ester which. when used as the starting material in the process of Example ](ii) gives the bis-benzyl ether of the title compound. Hydrogenolysis of this ether according to the procedure of Example l(iii) yields the title compound.

EXAMPLE 5 Preparation of l .4-dihydro-2,6-dimethyl-4-( 2-trifl uoromethylphenyl pyridine-3,S-diearboxylic acid bis (4-hydroxybutyl )ester.

Reaction of acetoacetic ester and 4 benzyloxybutanol according to the procedure of Example l(i) gives acetoaeetic acid 4-benzyloxybutyl ester which, when used as the starting material in the process of Example l(ii) gives the bisbenzyl ether of the title compound. Hydrogenolysis of this ether by the procedure of Example l(iii) yields the title compound.

What we claim is:

l. A 1.4-dihydropyridine compound of the formula:

HO-A-O-CO CO-O-A-OH wherein R is lower alkyl, R is hydrogen or methyl and A is a straight or branched alkylene chain the backbone of which contains from 2 to 4 carbon atoms.

2. A compound of claim 1, said compound being 1,4- dihydro- 2.6-dimethyl-4-( 2-trifluoromethylphenyl )-pyridine- 3,5-dicarboxylic acid bis (Z-hydroxyethyUester.

3. A compound of claim 1, said compound being 1.4- dihydrol ,2,6-trimethyl-4-( Z-trifluoromethylphenyl )-pyridine- 3,5-dicarboxylic acid bis (2-hydroxyethyl)ester.

4. A compound of claim 1, said compound being l.4- dihydro- 2 ,6-dimethyI-4-( Z-trifluoromethylphenyl )-pyridine- 3,5-dicarboxylic acid bis (3-hydroxy-2-propyl)ester. 

1. A 1,4-DIHYDROPYRIDINE COMPOUND OF THE FORMULA:
 2. A compound of claim 1, said compound being 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5 -dicarboxylic acid bis (2-hydroxyethyl)ester.
 3. A compound of claim 1, said compound being 1,4-dihydro-1,2,6-trimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5 -dicarboxylic acid bis (2-hydroxyethyl)ester.
 4. A compound of claim 1, said compound being 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5 -dicarboxylic acid bis (3-hydroxy-2-propyl)ester. 